The present invention relates to novel compounds, pharmaceutical compositions, and methods for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. In particular, the present invention relates to novel heterocyclyl-substituted ring-fused pyridine and pyrimidine compounds, pharmaceutical compositions containing such compounds and methods of use in treating psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of the compounds of the invention.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983), G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous-system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF inthese disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacclogy 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dosedependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.
PCT Patent Application WO 96/40142 discloses compounds useful in treatment of hyperproliferative diseases such as cancers and acnes, having the general formula shown below, 
wherein Z is NR1R2 and R1 is H and R2 is phenyl substituted by (R5)m or Q or R1R2N is a group of the formula 
PCT Patent Application WO 97/27199-A discloses 7H-pyrrolo [2,3-d]pyrimidine derivatives which are useful in treatment of cardiovascular disease, cerebrovascular disease and renal disease.
EP Patent Application EP0706795 discloses catechol diether compounds as inhibitors of tumor necrosis fact release, having the general formula shown below 
wherein Z can be benzimidazole substituted with quinoline. However, compounds of this type are not included in the compounds of the present invention.
U.S. Pat. No. 5,378,700 discloses fused pyrimidine derivatives useful for treatment of hypoxemia associated with respiratory diseases, having the general formula shown below 
wherein Y and Z together represent a fused biheterocyclic ring which has 1-3 N in any position being bonded via the N-atom to the 4-position of the pyrimidine. However, compounds of this type are not included in the compounds of the present invention.
CA Patent No. 2,011,222 discloses benzimidazole and azabenzimi-dazole derivatives useful for treatment of cardiovascular diseases and duodenal ulcers, having the general formula shown below 
wherein Y can be benzimidazole and Z can be phenyl or pyridyl. However, those compounds are not included in the compounds of the invention.
Insofar as is known, novel triazolopyridines and pyrimidines, which are described in detail below, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological disease, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
In accordance with one aspect, the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.
According to another aspect, the present invention provides novel compounds of formula (I) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of formula (I), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
According to yet another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals.
According to a still further aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:
Q is selected from the group consisting of: 
X is N or CR1;
Y, Z are independently N or CR2;
U, V are independently  greater than Cxe2x95x90G, CR13R14 or NR13, O, or S without formling Oxe2x80x94O, Sxe2x80x94O, or Sxe2x80x94S bonds;
G is O or S;
R1 is independently at each occurrence xe2x80x94H, halogen, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR9R10, xe2x80x94NR9COR9, xe2x80x94COR10, xe2x80x94OR10, SH or xe2x80x94S(O)nR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, where each a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl is each optionally substituted with halogen, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR9R10, xe2x80x94NR9COR9, xe2x80x94COR10, xe2x80x94OR10, SH or xe2x80x94S(O)nR12;
R2 is xe2x80x94H, halogen, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR9R10, xe2x80x94NR9COR9, xe2x80x94COR10, xe2x80x94OR10, SH or xe2x80x94S(O)nR12, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C7 cycloalkylalkyl, each optionally substituted with halogen, CN, C1-C4 haloalkyl, xe2x80x94NR9R10, NR9COR9, xe2x80x94COR10, xe2x80x94OR10, SH or xe2x80x94S(O)nR12;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl, where one carbon in any cycloalkyl ring may be replaced with O, S or NR9 and each C1-C10 alkyl, C2-C10 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94NHR6SO2R8, xe2x80x94OC(O)NR6R7, xe2x80x94N3, xe2x80x94OC(O)OR7, xe2x80x94CO2R8, xe2x80x94OC(O)R6, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R7, xe2x80x94CONR6R7, xe2x80x94CO2H, aryl, heteroaryl and heterocyclyl or xe2x80x94OR3a, xe2x80x94NR3aR3b, xe2x80x94NHR3a, xe2x80x94SOnR3a, xe2x80x94SO2NHR3a, xe2x80x94SO2NR3aR3b, xe2x80x94COR3a, xe2x80x94CONHR3a, xe2x80x94CONR3aR3b;
R3a, and R3b are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkylo, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl, where one carbon in any cycloalkyl mnay be replaced with O, S or NR9 and each C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, xe2x80x94SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R6, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R7, xe2x80x94NHR6SO2R8, xe2x80x94OC(O)NR6R7, xe2x80x94N3, xe2x80x94OC(O)OR7, xe2x80x94CONR6R7, xe2x80x94CO2H, aryl, heteroaryl and heterocyclyl;
L is a two to four atom saturated or partially unsaturated linker group optionally containing one to two B groups and in which one to two carbons of L may be  greater than Cxe2x95x90O or  greater than Cxe2x95x90S, where L may be substituted with one to three R4 groups;
R4 is independently selected in each occurrence xe2x80x94H, xe2x80x94CR10, xe2x80x94COR9, xe2x80x94CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S(O)nR12, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl, wherein C1-C6 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, are optionally substituted with the following functional groups: xe2x80x94OR10, xe2x80x94COR9, xe2x80x94CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S(O)nR12, halogen;
B is O, S(O)n or NR9;
A1-A4 are independently CR5, or up to two of A1-A4 can be N;
R5 is independently at each occurrence xe2x80x94H, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, xe2x80x94CO2R8, or xe2x80x94S(O)nR11, where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and wherein two adjacent R5 groups can form a 5-7 membered ring saturated on unsaturated optionally containing 1-2 O or SOn or 1-3 N heteroatoms optionally substituted with C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and not containing any Sxe2x80x94S, Oxe2x80x94O, Sxe2x80x94O or Nxe2x80x94S bonds in the ring;
R6 and R7 are independently at each occurrence H, C1-C6 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C12 bis(alkoxy)alkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, heteroaryl or heteroaryl(C1-C4 alkyl) or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R8 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl or heteroaryl(C1-C4 alkyl);
R9 and R10 are independently at each occurrence selected trom H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C6 alkoxyalkyl, C4-C7 cycloalkylalkyl;
R11 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), or xe2x80x94NR6R7;
R12 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R13 and R14, are independently at each occurrence H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl or heteroaryl(C1-C4 alkyl)xe2x80x94, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94CONR9, S (O)nR12;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, xe2x80x94SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, xe2x80x94SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 Etlkenyl, C2-C6 alkynyl, halogen, C1-C4 haloallkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R12, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R12, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
n is independently at each occurrence 0, 1 or 2 provided that:
(a) when Q is Ia, Ib or Ic and X is N, R1 is not H; and
(b) R1 is other than O-alkynyl or S-alkynyl;
[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Q is Ia, Ib, Ic;
X is N or CR1;
Y, Z are independently N or CR2;
U, V are  greater than Cxe2x95x90G, CR13R14, or NR13, O, or S without forming Oxe2x80x94O, Sxe2x80x94O, or Sxe2x80x94S bonds;
G is O;
R1 is independently at each occurrence H, C1-C4 alkyl, C3-C6 cycloalkyl, halogen, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94NR9COR10, C1-C4 haloalkyl, xe2x80x94COR10, xe2x80x94OR10 or xe2x80x94S(O)nR12;
R2 is independently at each occurrence xe2x80x94H, C1-C4 alkyl, C3-C6 cycloalkyl, halogen, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94NR9COR10, C1-C4 haloalkyl, xe2x80x94COR10, xe2x80x94OR10, or xe2x80x94S(O)nR12;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl, where one carbon in any cycloalkyl may be replaced with O, N or NR9 and each C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl is optionally substituted with 1 to 3 substituents in dependently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R6, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R71, xe2x80x94CONR6R7, xe2x80x94NHR6SO2R8, xe2x80x94OC(O)NR6R7, xe2x80x94N3, xe2x80x94OC(O) OR7, xe2x80x94CO2H, aryl, heteroaryl and heterocyclyl;
L is a linker selected from the group consisting of: CR42CR42CR42, CR42CR4xe2x95x90CR4, CR42CR42, CR4xe2x95x90CR4, CR42CR42B, CR4xe2x95x90CR4B;
R4 is independently selected in eaech occurrence xe2x80x94H, xe2x80x94OR10, xe2x80x94COR9, xe2x80x94CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S(O)nR12, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl, each option ally lubstituted with the following functional groups: xe2x80x94OR10, xe2x80x94COR9, CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S(O)nR12, halogen, or two R4 taken together form one or two carbonyl(s) or thiocarbonyl, (s);
B is O, S(O)n, NR12;
A1-A4 are CR5;
R5 is independently at each occurrence xe2x80x94H, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, xe2x80x94CO2R8, or xe2x80x94S(O)nR11, where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and wherein two adjacent R5 groups can form a 5-7 membered ring saturated on unsaturated optionally containing 1-2 O or SOn or 1-3 N heteroatoms optionally substituted with C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, NR6COR7, NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and not containing any Sxe2x80x94S, Oxe2x80x94O, Sxe2x80x94O or Nxe2x80x94S bonds in the ring;
R6 and R7 are independently at each occurrence H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, heteroaryl or heteroaryl(C1-C4 alkyl)xe2x80x94; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R8 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl or heteroaryl(C1-C4 alkyl);
R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R11 is C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl or heteroaryl(C1-C4 alkyl), piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R12 is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R13 and R14 are independently H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl or heteroaryl(C1-C4 alkyl)xe2x80x94, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94CONR9, xe2x80x94S(O)nR12;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl , pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
n is independently at each occurrence 0, 1 or 2;
[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Q is IIa, IIb, or IIc;
X is N or CR1;
Y, Z are independently N or CR2;
U, V are  greater than Cxe2x95x90G, CR13R14, or NR13, O, or S without forming Oxe2x80x94O, Sxe2x80x94O, or Sxe2x80x94S bonds;
G is O;
R1 is independently at each occurrence H, C1-C4 alkyl, C3-C6 cycloalkyl, halogen, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94NR9COR10, C1-C4 haloalkyl, xe2x80x94COR10, xe2x80x94OR10 or xe2x80x94S(O)nR12;
R2 is independently at each occurrence H, C1-C4 alkyl, C3-C6 cycloalkyl, halogen, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94NR9COR10, C1-C4 haloalkyl, xe2x80x94COR10, xe2x80x94OR10 or xe2x80x94S(O)nR12;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl, where one carbon in any cycloalkyl may be replaced with O, S or NR9 and each C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, C5-C10 cycloalkenylalkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R6, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, heteroaryl and heterocyclyl;
L is a linker selected from the group consisting of: R42CR42CR42, CR42CR4xe2x95x90CR4, CR42CR42, CR4xe2x95x90CR4, CR42CR42B, CR4xe2x95x90CR4B;
R4 is independently selected in each occurrence xe2x80x94H, xe2x80x94OR10, xe2x80x94COR9, xe2x80x94CO2R8, xe2x80x94CNR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S((O)nR12, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl, each optionally substituted with the following functional groups: xe2x80x94OR10, xe2x80x94COR9, CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, S(O)nR12, halogen, or two R4 taken together form one or two carbonyl(s) or thiocarbonyl (s);
B is O, S(O)n, NR12;
A1-A4 are CR5;
R5 is independently at each occurrence xe2x80x94H, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, xe2x80x94CO2R8, or xe2x80x94S(O)nR11, where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and wherein two adjacent R5 groups can form a 5-7 membered ring saturated on unsaturated optionally containing 1-2 O or SOn or 1-3 N heteroatoms optionally substituted with C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, NR6COR7, NR6CO2R8, xe2x80x94COR6, xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and not containing any Sxe2x80x94S, Oxe2x80x94O, Sxe2x80x94O or Nxe2x80x94S bonds in the ring;
R6 and R7 are independently at each occurrence H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, heteroaryl or heteroaryl(C1-C4 alkyl)xe2x80x94; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R8 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl), heteroaryl or heteroaryl(C1-C4 alkyl);
R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R11 is C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, heteroaryl or heteroaryl(C1-C4 alkyl), piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
R12 is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R13 and R14 are independently H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)xe2x80x94, heteroaryl or heteroaryl(C1-C4 alkyl)xe2x80x94, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94CONR9, xe2x80x94S(O)nR12;
aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8. xe2x80x94NR9R10, and xe2x80x94CONR9R10;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR10, SH, xe2x80x94S(O)nR12, xe2x80x94COR12, xe2x80x94CO2R8, xe2x80x94OC(O)R12, xe2x80x94NR9COR9, xe2x80x94N(COR12)2, xe2x80x94NR9CONR9R10, xe2x80x94NR9CO2R8, xe2x80x94NR9R10, and xe2x80x94CONR9R10;
n is independently at each occurrence 0, 1 or 2;
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein: Q is Ia and X is N.
[5] In a still more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Y and Z are N or CR2;
R1 is independently at each occurrence xe2x80x94Me, xe2x80x94Et, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OMe, xe2x80x94SMe, xe2x80x94NHMe, xe2x80x94NMe2, xe2x80x94COMe, xe2x80x94SOMe, xe2x80x94SO2Me;
R2 is xe2x80x94H, xe2x80x94Me, halogen;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C10 cycloalkylalkyl, C2-C10 alkoxyalkyl, cycloalkenyl, cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, xe2x80x94SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R10, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R7, xe2x80x94CO2H, xe2x80x94CONR6R7;
L is CH2CR42CR42, CR42CR4xe2x95x90CR4, CR42CR42, CR4xe2x95x90CR4, CR42CR42B, CR4xe2x95x90CR4B, where R4 is H, or C1-C2, substituted with the following functional groups: xe2x80x94CF3, xe2x80x94OMe, xe2x80x94COMe, xe2x80x94CO2Me, xe2x80x94CONHMe, xe2x80x94CN, xe2x80x94NMe2, xe2x80x94SMe, xe2x80x94SOMe, xe2x80x94SO2Me, halogen, or two R4 taken together form a carbonyl;
B is O, S, SO, SO2, NH, NMe;
A1-A4 are CR5,
R5 is independently at each occurrence xe2x80x94H, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C10 alkenyl, C2C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, xe2x80x94CO2R8, or xe2x80x94S(O)nR11, where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and wherein two adjacent R5 groups can form a 5-7 membered ring saturated on unsaturated optionally containing 1-2 O or SOn or 1-3 N heteroatoms optionally substituted with C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, xe2x80x94NR6R7, NR6COR7, NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO2R8, xe2x80x94CO(NOR9)R7, or xe2x80x94S(O)nR11 and not containing any Sxe2x80x94S, Oxe2x80x94O, Sxe2x80x94O or Nxe2x80x94S bonds in the ring;
R6, R7, R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R8 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl;
R11is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
[6] In a further preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Y and Z are N;
R1 is xe2x80x94Me or halogen;
R2 is xe2x80x94H, xe2x80x94Me, halogen;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C10 cycloalkylalkyl, C2-C10 alkoxyalkyl, cycloalkenyl, cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, xe2x80x94SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R10, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R7, xe2x80x94NHR6SO2R8, xe2x80x94CO2H, xe2x80x94OC(O)NR6R7, xe2x80x94N3, xe2x80x94OC(O)OR7, xe2x80x94CONR6R7;
L is a linker selected from the group consisting of: CH2CH2CH2, CH2CH2, CHxe2x95x90CH, CH2CH2O;
A1, A2, A3 and A4 are carbon substituted independently at each occurrence with R5;
R5 is independently at each ocurrence H, C1-C6 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 alkoxy, xe2x80x94NO2, halogen, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR11 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, xe2x80x94CO2R8, or xe2x80x94S(O)nR11;
R6, R7, and R9 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R8, R11are independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl;
[7] In another preferred embodiment, the present invention provides a novel compound of formula I,
wherein the compound is selected from the group:
(R,S)-4-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
(R,S)-4-(5,7-dichloro-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(7-chloro-5-methylsulfonyl-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(7-chloro-5-methoxy-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(7-chloro-5-methyl-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(7-chloro-5-ethyl-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(7-chloro-5-cyano-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(5-acetyl-7-chloro-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine;
4-(7-chloro-5-thiomethyl-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine; and
4-(7-chloro-5-methylsulfonyl-2,3-dihydro-4-indol-1-yl)-1-[1-methoxyethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyrimidine.
[8] In another more preferred embodiment, the present invention provides a novel compound of formula I, wherein: Q is Ia and X is CR1.
[9] In another more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Y and Z are N or CR2;
R1 is independently at each occurrence xe2x80x94Me, xe2x80x94Et, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OMe, xe2x80x94SMe, xe2x80x94NHMe, xe2x80x94NMe2, xe2x80x94COMe, xe2x80x94SOMe, xe2x80x94SO2Me;
R2 is xe2x80x94H, xe2x80x94Me, halogen;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C10 cycloalkylalkyl, C2-C10 alkoxyalkyl, cycloalkenyl, cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, xe2x80x94SH, xe2x80x94S(O)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R10, xe2x80x94NR7COR6, xe2x80x94CO2H, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R7, xe2x80x94NHR6SO2R8, xe2x80x94OC(O)NR6R7, xe2x80x94N3, xe2x80x94OC(O)OR7 and xe2x80x94CONR6R7;
L is a linker selected from the group consisting of: CH2CR42CR42, CR42CR4xe2x95x90CR4, CR42CR42, CR4xe2x95x90CR4, CR42CR42B, CR4xe2x95x90CR4B, where R4 is H, or C1-C2, substituted with the following functional groups: xe2x80x94CF3, xe2x80x94OMe, xe2x80x94COMe, xe2x80x94CO2Me, xe2x80x94CONHMe, xe2x80x94CN, xe2x80x94NMe2, xe2x80x94SMe, xe2x80x94SOMe, xe2x80x94SO2Me, halogen, or two R4 taken together form a carbonyl;
R4 is independently selected in each occurrence xe2x80x94H, xe2x80x94OR10, xe2x80x94COR9, xe2x80x94CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S(O)nR12, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl, each optionally substituted with the following functional groups: xe2x80x94OR10, xe2x80x94COR9, CO2R8, xe2x80x94CONR9R10, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94S(O)nR12, halogen, or two R4 taken together form one or two carbonyl(s) or thiocarbonyl(s);
B is O, S, SO, SO2, NH, NMe;
A1-A4 are CR5,
R5 is independently at each occurrence H, C1-C6 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, xe2x80x94NO2, halogen, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR6R7, NR6COR7, NR6CO2R8, xe2x80x94COR11 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, CO2R8, or xe2x80x94S(O)nR11, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl and C4-C8 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, xe2x80x94NO2, halo, xe2x80x94CN, xe2x80x94NR6R7, xe2x80x94NR6COR7, NR6CO2R8, xe2x80x94COR6 xe2x80x94OR7, xe2x80x94CONR6R7, CO2R8, xe2x80x94CO(NOR9)R7 and xe2x80x94S(O)nR11;
R6, R7, R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R8 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl;
R11is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl.
[10] In another still more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
Y and Z are N;
R1 is xe2x80x94Me or halogen;
R2 is xe2x80x94H, xe2x80x94Me, halogen;
R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl or C4-C10 cycloalkylalkyl, C2-C10 alkoxyalkyl, cycloalkenyl, cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, halogen, C1-C4 haloalkyl, cyano, xe2x80x94OR7, xe2x80x94SH, xe2x80x94S(Q)nR11, xe2x80x94COR6, xe2x80x94CO2R8, xe2x80x94OC(O)R10, xe2x80x94NR7COR6, xe2x80x94N(COR6)2, xe2x80x94NR7CONR6R7, xe2x80x94NR7CO2R8, xe2x80x94NR6R7, xe2x80x94CO2H, xe2x80x94NHR6SO2R8, xe2x80x94OC(O)NR6R7, xe2x80x94N3, xe2x80x94OC(O)OR7, xe2x80x94CONR6R7;
L is a linker selected from the group consisting of: CH2CH2CH2, CH2CH2, CHxe2x95x90CH, CH2CH2O;
A1, A2, A3 and A4 are carbon substituted independently at each occurrence with R5;
R5 is independently at each ocurrence H, C1-C6 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 alkoxy, xe2x80x94NO2, halogen, xe2x80x94CN, C1-C4 haloalkyl, xe2x80x94NR6R7, xe2x80x94NR6COR7, xe2x80x94NR6CO2R8, xe2x80x94COR11 xe2x80x94OR7, xe2x80x94CONR6R7, xe2x80x94CO(NOR9)R11, xe2x80x94CO2R8, or xe2x80x94S(O)nR11;
R6, R7, and R9 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl;
R8, R11are independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl;
[11] In another preferred embodiment, the present invention provides a novel compound of formula I, wherein the compound is selected from the group:
(S)-4-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5,7-dibromo-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(5,7-dimethoxy-2,3-dihydro-1H-indol-1-yl)1-[1-ethylpropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5-bromo-7-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5-bromo-7-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5-bromo-7-methyl-2,3-dihydro-1H-indolyl)-1-[1-(methoxymethy)lpropyl-6-methyl-1H-1,2,3-triazolo(4,5-c]pyridine;
(R,S)-4-(5-bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-1-[1-methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5-bromo-7-chloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(S)-4-(7-chloro-5-methoxy-2,3-dihydro-1 H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-methyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxyinethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-ethyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-cyano-2,3-dihydro-1H-indol-[1-yl)-1-1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-thiomethyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethy)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-methyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethy)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-ethyl-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethy)propy1]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(7-chloro-5-cyano-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethy)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-thiomethyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-methylsulfonyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-methyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-ethyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-cyano-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(5-acetyl-7-chloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(7-chloro-5-methylsulfonyl-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxymethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(methoxyethyl)-3-methoxypropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-[1-(cyanomethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(7-chloro-5-methoxy-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(7-chloro-5-methyl-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(7-chloro-5-ethyl-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(7-chloro-5-cyano-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(5-acetyl-7-chloro-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(7-chloro-5-thiomethyl-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
N-(7-chloro-5-methylsulfony-1H-indol-1-yl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine;
(R,S)-8-chloro-1,2,3,4-tetrahydro-1-[1-[1-(methoxymethy)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
(R,S)-8-bromo-1,2,3,4-tetrahydro-1-[1-[1-(methoxymethy)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
(R,S)-8-chloro-6-methoxy-1,2,3,4-tetrahydro-1-[1-[1-(methoxymethy)propyl]-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
(R,S)-8-chloro-6-cyano-1,2,3,4-tetrahydro-1-[1-[1-(methoxymethy)propyl]-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
(R,S)-8-chloro-1,2,3,4-tetrahydro-1-[1-[1-(methoxymethy)propyl]-6-methylsulfonyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
8-chloro-1,2,3,4-tetrahydro-1-[1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
8-bromo-1,2,3,4-tetrahydro-1-[1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
8-chloro-1,2,3,4-tetrahydro-1-[1-(1-ethylpropyl)-6-methoxy-1H-1,2,3-triazolo[4,5-clpyridin-4-yl]-6-methylquinoline;
8-chloro-6-cyano-1,2,3,4-tetrahydro-1-(1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
8-chloro-1,2,3,4-tetrahydro-1-[1-(1-ethylpropyl)-6-methylsulfonyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline;
6-acetyl-8-chloro-1,2,3,4-tetrahydro-1-[1-(1-ethylpropyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-6-methylquinoline; and
(R,S)-5-bromo-3,4-dihydro-4-[1-[1-(methoxymethyl)propyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-yl]-7-methyl-2H-1,4-benzoxazine.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compounds of Formula (I) as described above.
The present invention further comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in maamals comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) as described above.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included withinthis term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids,such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peotides, 5: 342-429, the teaching of which is hereby incorporated by reference. Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5, -triiodothyronine, and 3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid. The term xe2x80x9camino acid residuexe2x80x9d as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non- toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. For example, such conventional non- toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
The bicylic fused pyrimidine and pyridines of this invention can be prepared by one of the general schemes outlined below (Schemes 1-15).
Compounds of the Formula (I) wherein X and Y are N and Z is NR3, and 
can be prepared as shown in Scheme 1. 
The 4,6-dihydroxypyrimidines (III) can be nitrated using fuming nitric acid and then converted into intermediates (IV) by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylanilines (see: Brown, D. J. et.al. J. Chem. Soc., 1954, 3832). The amino group of pyrimidines of Formula (V) can be prepared from the corresponding nitro compounds (IV) by treatment with reducing agents such as, but not limited to, sodium dithionate, iron or zinc, or catalytic hydrogenation (see: Larock, R. C. Comprehensive Organic Transformations, VCH Publishers, New York, 1989, 411). Reaction with compounds of Formula xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 (XV), can be used to provide compounds of Formula (VI). Conditions which may facilitate this transformation include the optional presence of protic or aprotic acids, or bases such as alkali metal hydrides, trialkylamines, or alkali metal carbonates, or alkali metal bis(trimethylsilyl)amides wherein the metal can be sodium, lithium, or potassium. These reactions may be conducted neat, or in the optional presence of solvents such as but not limited to cyclic ethers such as tetrahydrofuran, dialkylformamides, ethylene glycol, 2-ethoxyethanol, halocarbons, alkanenitriles, or alkyl alcohols at room temperature or at elevated temperature up to the boiling point of the solvent employed. One skilled in the art of organic synthesis will readily understand the optimal combinations of these conversions to prepare a number of compounds of Formula (VI). Treatment of compound of Formula (VI) with primary amines then can provide the intermediates (VII) using reaction conditions similar to those employed for the conversion of (V) to (VI). Cyclization to triazolopyrimidines of Formula (I) can then be readily accomplished by diazotization and cyclization of the diamino compounds of Formula (VII) with an alkali metal nitrite in the presence of acid in water with or without an organic cosolvent such as halocarbons, or cyclic ethers.
Alternatively, compounds of Formula (I) wherein X and Y are N and Z is NR3, of this invention can be prepared as outlined in Scheme 2: 
Treatment of compound of Formula (V) with primary amines can provide the diamino substituted pyrimidines (VIII). Conditions which facilitate this transformation are detailed previously for the conversion of (VI) to (VII). Cyclization to triazolopyrimidines of Formula (VIII) can then be readily accomplished by following the conditions already described for the conversion of (VII) to (I) in Scheme 1. The leaving group such as, but not limited to, halogen can then be displaced by addition of xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94O to provide compounds of Formula (I) by utilizing the conditions described for the conversion of (V) to (VI).
Compounds of the Formula (VI) can also prepared by an another approach (Scheme 3) involving addition of xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 to (IV) to afford compounds of Formula (XI). 
The nitro group in (XI) can be reduced to give compounds of Formula (VI) under conditions similar to those described for the transformation of (IV) to (V) in Scheme 1. Alternatively, as shown in Scheme 3, addition of xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 to compounds of Formula (IV) can generate in-situ the pyrimidones (X). For example, treatment of dichloropyrimidines of Formula (IV) with one equivalent of xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 in the presence of solvents such as (but not limited to) dialkylsulfoxides, dialkylformamides, and alkyl alcohols readily generate pyrimidones (X). Compounds of Formula (X) can be converted into (XI) by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylanilines with or without an inert solvent. Compounds of Formula (XI) can be reduced to give (IV) under conditions described in Scheme 1. Compounds of Formula (VI) are elaborated to structures of Formula (I) as previously shown in Scheme 1.
Scheme 4 outlines another route to fused triazolopyrimidine type of compounds of this invention. 
4,6-dihydroxy-5-nitropyrimidines can be treated with aryl sulfonic anhydrides, aryl sulfonyl chlorides, alkyl sulfonic anhydrides or alkyl sulfonyl chlorides in the presence or absence of bases such as alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides, dialkylacetamides at temperatures ranging from 0xc2x0 to 200xc2x0 C. to give intermediates of Formula (XII). Compounds of Formula (XII) are treated with primary amines to give aminonitropyrimidines (XIII). Treatment of (XIII) with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 can provide compounds of Formula (XIV). Compounds of the formula (XIV) can be reduced to amino derivatives (VII) using the reagents described for the conversion of (IV) to (V) in Scheme 1. Intermediate (VII) can be converted to (I) (X and Y are N; Z is NR3) by diazotization and cyclization as delineated in Scheme 1.
Fused imidazolopyrimidines of the Formula (I) wherein X is N, Y is CR2, and Z is NR3, can be prepared from compound (VIII) as shown in Scheme 5. 
Treatment of (VIII) with an acylating agent such as, but not limited to, alkyl anhydrides, haloalkyl anhydrides, alkylamides, haloalkyl amides, trialkylorthoesters R2(OR)3 (where R is C1-C4 alkyl), iminoesters, guanidines, cyanogen bromide, R2COOH, urea or thiourea in the presence or absence of an acid (such as HOAc, HCl, H2SO4) in the presence or absence of an organic cosolvent such as alkyl alcohols, cyclic ethers, or aromatic solvents at temperatures ranging from 0xc2x0 to 200xc2x0 C. gives compounds of Formula (XVI). Treatment of (XVI) with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 can provide imidazolopyrimidine (I, wherein X is N, Y is CR2, Z is NR3).
The method of synthesis of the triazolopyridines of this invention is shown in Scheme 6. 
The 4-hydroxy group in (XVII) can be converted into chloro by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylaniline (see: Brown, D. J. et.al. J. Chem. Soc., 1954, 3832) to afford compounds of Formula (XVIII). Addition of primary amines to compound (XVIII) can provide alkylaminonitropyridines (XIX). The nitro group in (XIX) can be reduced using the conditions employed for the transformation of (IV) to (V) in Scheme 1 to give (XX). Diazotization and cyclization of (XX) can provide chlorotriazolopyridine derivatives (XXI) as was described for the conversion of (VI) to (VII) in Scheme 1. The chloro group can then be displaced by addition of xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 to afford compounds of Formula (I).
Imidazolopyridines of the present invention can be prepared from compound (XX) as shown in Scheme 6 by following the conditions outlined for the conversion of (VIII) to (XVI) in Scheme 5. Treatment of compound (XXII) with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 using the conditions outlined in Scheme 1 can provide compounds of Formula I.
Alternatively, the triazolopyridines and imidazolopyridines can be synthesized as shown in Scheme 7. Treatment of compounds of Formula (XVII) with an aliphatic or aromatic amine in the appropriate organic solvent but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF gives the corresponding ammonium salt, which upon treatment with POCl3 at temperatures from 25 to 120xc2x0 C., give compounds of Formula (XXIII). Treatment of compounds of Formula (XXIII) with appropriate primary amines in an organic solvent such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF, dialkylsulfoxides at temperatures from 25 to 120xc2x0 C. to give (XXIV). This was converted to (XIX) by treatment with POCl3 at temperatures from 25 to 120xc2x0 C. 
Compounds of Formula (XIX) could be coupled with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 with or without the presence of solvent at temperatures from 25 to 200xc2x0 C. to give product (XXV). These could be converted to intermediates (XXVI) by reduction of the nitro group under a variety of reducing conditions, such as those used for the conversion of (IV) to (V) in Scheme 1. The final cyclization was carried out as described for the conversion of (VII) to (I) in Scheme 1. Compounds of Formula (XIX) can be converted to intermediates (XX) by reduction of the nitro group under a variety of reducing conditions, such as those used for the conversion of (IV) to (V) in Scheme 1. Diazotization and cyclization of (XX) can provide chlorotriazolopyridine (XXI) as was described for the conversion of (VII) to (I) in Scheme I. The chloro group can then be displaced by addition of xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 in the presence of a base in an inert solvent. Bases include, but are not limited to, alkali metal alkoxides, akali metal hydrides, trialkyl amines, pyridine, 4-dimethylaminopyridine, alkali metal dialkyl amides or alkali metal bis(trimethylsilyl)amides. Inert solvents include, but are not limited to, halocarbons, alkanenitriles, dialkylformamides, dialkylacetamides, dialkyl ethers, cyclic ethers such as tetrahydrofuran or dioxane, or alkyl alcohols. The addition can take place in the presence of an acid such as but not limited to HCl, H2SO4, AcOH, methanesulfonic acid, p-toluenesulfonic acid in inert solvents such as toluene, xylenes at temperatures ranging from 0xc2x0 to 200xc2x0 C. to afford product I. The same transformation can be affected under thermal conditions, neat, or in the presence of a high boiling solvent.
Imidazolopyridines can be synthesized from intermediates of Formula (XXII) as described in Scheme 6.
Compounds of general Formula (I, Q is Ib) may be prepared according to the procedures outlined in Scheme 8. 
Intermediates of Formula (VIII), (XX) or (XIII) may be converted to compounds of Formula (XXVII) by treatment with an acylating agent in the presence or absence of a base in an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 200xc2x0 C. Acylating agents include, but are not limited to, phosgene, thiophosgene, diphosgene, triphosgene, carbonyl diimidazole, thiocarbonyl diimidazole, dialkylcarbonates (such as diethyl carbonate) or RaRbN(Cxe2x95x90G)ORc (where G is O, S; Ra, Rb, and Rc are independently C1-C8 alkyl). Bases include, but are not limited to, alkali metal alkoxides, akali metal hydrides, trialkyl amines, pyridine, 4-dimethylaminopyridine, alkali metal dialkyl amides or alkali metal bis(trimethylsilyl)amides. Inert solvents include, but are not limited to, halocarbons, alkanenitriles, dialkylformamides, dialkylacetamides, dialkyl ethers, cyclic ethers such as tetrahydrofuran or dioxane, or alkyl alcohols. Intermediates of Formula (XXVII) may be converted to compounds of Formula (XXVIII) (Formula (I), where Q is Ib and R13 is H) by reaction with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94, using the conditions described for the conversion of compound (V) to (VI) in Scheme 1. Compounds of Formula (XXVIII) may be converted to compounds of (Formula (I), where Q is Ib) by treatment with R13L (where L is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. Bases include, but are not limited to, alkali metal alkoxides, akali metal hydrides, trialkyl amines, pyridine, 4-dimethylaminopyridine, alkali metal dialkyl amides or alkali metal bis(trimethylsilyl)amides. Inert solvents include, but are not limited to, halocarbons, alkanenitriles, dialkylformamides, dialkylacetamides, dialkyl ethers, cyclic ethers such as tetrahydrofuran or dioxane, or alkyl alcohols.
Compounds of Formula (XXIX) may be prepared from compounds of structure (XXVII) by reaction with R13L (where L is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. Bases and inert solvents may be the same as those listed above for the preparation of compounds of Formula (I), (where Q is Ib) from (XXVIII). Intermediates of Formula (XXIX) can be reacted with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 to give compounds of Formula (I), (where Q is Ib) using the conditions described for the conversion of compound (V) to (VI) in Scheme 1.
Alternatively intermediates of Formula (VII) and (XXVI) can be converted to compounds of Formula (XXVIII) under similar conditions that may by used for the conversion of (VIII), (XX) or (XIII) to (XXVII).
As shown in Scheme 9, reactionof a 4-alkylamino-3-nitro-pyridone of Formula (XXIV) with a reducing agent, such as Na2S2O4 affords the corresponding 4-amino-3-amino-pyridone of Formula (XXX). This transformation can be effected under a variety of reducing conditions, such as catalytic hydrogenation, reducing metal reaction (Fe, Sn, Zn), hydride reaction (NaBH4, LiAlH4) etc., which are known to those skilled in the art. The 4-amino-3-amino-pyridone can be converted to the triazolopyridone of formula (XXXI) by treatment with an alkali metal nitrite, such as NaNO2, under acidic conditions. The resulting triazolopyridone can be converted to the corresponding halo-triazolopyridine of Formula (XXXII)(X is Cl or Br), by treatment with a halogenating agent such as POCl3, PBr3, POBr3. Alternatively X can be an appropriate leaving group resulting from treatment of the triazolopyridone with triflic, tosic or mesyl anhydride in the presence of a base. The triazolopyridine can be coupled with arylamines xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 under acidic, basic or thermal catalysis (conditions described in Scheme 7) to compounds of Formula I. 
The R5 substituents on the aryl ring can be further modified by reactions described in Scheme 10. 
The dibromo analog (XXXIII) of Formula (I) (where X is CH, Y is N, L is CH2xe2x80x94CH2) was treated with an alkyllithium such as n-butyllithium in an aprotic solvent at low temperature to affect Br/Li exchange. The aryllithium intermediate was further reacted with an electrophile to give the 7-substituted analog (XXXIV). Alternatively the 5-bromo substituent of the indoline could selectively react with various vinyltrialkyltin, vinylboronic acid reagents, or thiol salts in the presence of a palladium catalyst to give the 5-substituted analogs of Formula (XXXV). These analogs could be further reacted with an alkyllithium followed by an electrophile to give analogs of Formula (XXXVIII). Compounds of Formula (XXXIII) could be converted to the 7-methoxy analogs (XXXVI) by treatment with MeONa/MeOH in DMF under copper (I) salt catalysis. The 5-bromo substituent of these analogs could be further elaborated by the employing conditions described for the transformation of (XXXV) to (XXXVIII). In all cases the indoline ring may be dehydrogenated to the corresponding indole analogs by employing known methods described in the chemical literature.
Compounds of Formula I may be synthesized as described in Scheme 11. 
Coupling a suitably substituted aniline having an ortho xe2x80x94Br, xe2x80x94I, or xe2x80x94OSO2CF3 group with a triazolopyridine of Formula (XXXII) under base, acid or thermal catalysis gives the coupled product of Formula (XXXIV). The central nitrogen of (XXXIV) was allylated by treatment with a base such as NaH in an aprotic solvent to give (XXXV). This in turn may be subjected to a palladium-catalyzed ring closure (see: Larock, R. C et. al. Tetrahedron Let., 1987, 44, 5291) to give compounds of Formula (I) (L is xe2x80x94CHxe2x95x90CRxe2x80x94).
Alternatively other analogs with the Formula (I) can be obtained by transformations described on Scheme 12.
Reaction of compounds of Formula (XXXIV) with a suitably substituted acetylene using a suitable palladium catalyst (see: Heck, R. F. et. al. Acc. Chem. Res., 1979, 12, 146) may provide the corresponding acetylenic aryls of Formula (XXXVI). Depending on the original substitution on the acetylene, compounds of Formula (XXXVI) can be converted to the 2-alkylindole analogs (Formula I in which L is xe2x80x94CRxe2x95x90CHxe2x80x94), or the indolinones (Formula I in which L is xe2x80x94COxe2x80x94CH2xe2x80x94). 
An alternative method for the introduction of various side chains is described in Scheme 13: 
The benzyltriazolopyridine or pyrimidine (XXXVII) may be synthesized by one of the previously described Schemes. The benzyl group is cleaved by the action of a strong acid or Lewis acid such as AlCl3 and the resulting system of Formula (XXXVIII) is alkylated by treatment with a strong base, followed by an electrophile, or by a method described for the introduction of a functional group on a triazole by Katrinsky, A. R in Comprehensive Heterocyclic Chemistry the Structure, Reactions Synthesis and Uses of Heterocyclic Compounds and Comprehensive Heterocyclic Chemistry II: a review of the literature, 1982-1995: the Structure, Reactions Synthesis and Uses of Heterocyclic Compounds to give compounds of Firmula (I). Pyrazolo-, imidazolo, and indolo analogs can be synthesized in an analogous manner. Other heterocyclic linkers may be synthesized by methods described in the above references.
Other ring systems of the present invention can be synthesized according to Scheme 14: 
The cyano compounds of Formula (XXXIX) may be condensed with hydrazine to give compounds of Formula (XL). These may be condensed with amidines, followed by a cyclization with a carbonate in the presence of a base to give compounds of Formula (XLI). Compounds of Formula (XLI) may be converted to the chlorode (XLII) and further coupled with compounds xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 to give compounds of Formula (XLIII) or (XLIV), depending on the structure of the starting compounds of Formula (XXXIX).
Another ring system of this invention may be synthesized as shown in Scheme 15. 
The known pyrazines (see:Huynh-Dinh et. al. J. Org. Chem. 1979, 44, 1028) of Formula (XLV) could be converted to the fused systems of Formula (XLVI) via the action of an triethylorthoester. Compounds of Formula (XLVI) could be coupled with compounds xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 to give compounds of Formula (I), (where Q is IIc).
Pyrazolopyrimidines (LI) of the present invention may be readily synthesized by following the reaction sequence outlined in Scheme 17 shown below. 
Alkylhydrazines of the type (XXXXII) were readily prepared by reacting ketone (XXXIX) with acetylhydrazide or t-butylcarbazate (XXXX) to afford hydrazone (XXXXI) which can readily be reduced using catalytic hydrogenation or by treatment with borane to give (XXXXII). XXXXII can readily be converted to XXXXIII in the presence of aq. acid (see: N. I Ghali et al J. Org. Chem. 1981, 46, 5413-14 and Boissier et al French patent M4306, 1966). Alternatively alkylhydrazines (XXXXIII) may be readily prepared from amines (XXXXIV) using hydroxylamine-O-sulfonic acid in the presence of base (See Gever et al. J. Org. Chem. 1949, 14, 813). Treatment of compound (XXXXIII) with ethylidine malononitrile (XXXXV) in alcohol medium in the presence or absence of base such as alkylamines to afford pyrazole derivative (XXXXVI). The nitrile group in the pyrazole derivative can readily be hydrolyzed using acids such as sulfuric acid, to give pyrazole carboxamide derivative (XXXXVII). Alternatively pyrazole carboxamides (XXXXVII) can be prepared by reacting (XXXXIII) with (XXXXVIII) in solvents such as alcohol in the presence of a base. Pyrazolopyrimidones of the formula (XXXXIX) can be obtained by treatment with esters in the presence of a base such as alkali metal alkoxides in refluxing alcohol (for example, see: Miyashita et al, Heterocycles, 1996, 42(2), 691). The hydroxy group of pyrazolopyrimidones (XXXXIX) can be converted to a leaving group Y (eg. tosylate, mesylate, triflate, or halogen) using classical organic group transformations to afford formula (L). Formula (L) can readily be converted to compounds of the present invention (LI) upon treatment with xe2x80x94Arxe2x80x94Lxe2x80x94NHxe2x80x94 either as a neat reaction mixture at elevated temperatures or in the presence of a base in solvents such as THF, alkyl ethers or dialkylformamides.
Other ring systems can be synthesized by methods described in EP 0 778277 A1, WO 9413677 and WO 9413696.